This invention is directed to synthetically produced short peptide sequences which inhibit HIV-1 gp120 induced neuronal cell death, for use in preventing neurological deterioration in patients suffering from AIDS as well as other neurological degenerative diseases.
Among the symptoms and conditions associated with HIV infection (AIDS) are specific neurological conditions which can be termed xe2x80x9cneuro-AIDSxe2x80x9d.
Neuro-AIDS, whose incidence and severity appears to be increasing, can manifest itself in many forms including encephalopathies, neuropathies, memory loss, dementia, depression, psychosis and opportunistic infections. One explanation for AIDS associated neuropathologies, which can include infiltration of infected immune cells, white matter aberrations, reduced dendritic and axonal arborization, and neuronal loss is that dissociated HIV envelop protein, gp120, which has been shown to be secreted abundantly by infected macrophages and is present in plasma and CSF, contributes to pathogenesis via receptor-mediated interactions with various shared cell surface receptors on brain and immune cells.
There is growing evidence that neurotoxicity and infectivity associated with HIV have distinctive attributes suggesting divergence of mechanism. In particular, HIV infection does not occur in rodents and does not require signaling, while the biological activities associated with the envelope protein can be demonstrated in both human and rodent cells and requires signaling. The neurotoxic action of HIV-1 envelope protein gp120 is potent and requires the presence of glial cells, which may then secrete neurotoxic products or cytokines. In rodents, intraventriculary administered gp120 produces endocrine abnormalities.
The neuropeptide vasoactive intestinal peptide (VIP), as well as homologous short (5-8 residues) peptides derived from the gp120 V2 region derived peptides (8-10) are inhibitors of gp120 neurotoxicity. In neonatal rats, delayed behavioral milestones and abnormal neuronal dearborization produced by administration of nanogram quantities of gp120 are also prevented by VIP (II) and gp120 V2-region derived peptide T (xe2x80x9cDAPTAxe2x80x9d). In the same study, toxic fragments of gp120 were recovered from treated animals, suggesting that some of the neural damage is attributable to proteolytic products of the HIV envelope.
Alzheimers"" Disease or dementia is believed to be caused by the deterioration of the cholinergic neurons in the basal forebrain. VIP is co-localized with cholinergic neurons in the basal forebrain and is believed to maintain neuronal survival. In a proposed secondary phase of Alzheimers"" disease, endogenous neurons of the cortex of various different chemical types degenerate following deprivation of their vasoactive intestinal polypeptide neuronal growth factor once contained in the cholinergic endings.
In U.S. Pat. No. 5,567,682, short chain peptides, specifically peptide T and related analogs, are described for treating the symptoms of Alzheimers"" disease by reducing or halting a loss of neurons. Similarly, these peptides are described as being useful in inhibiting HIV-1 binding to T4 cell receptors (U.S. Pat. No. 5,276,016).
Recent discoveries show that HIV gp120 uses a number of chemokine co-receptors, in conjunction with CD4, to allow viral entry of target cells. Moreover, various gp120""s can block binding of specific chemokine ligands with the CCR5 receptor. Chemokine receptors, first characterized on activated immune cells, have been shown to also be present on cerebellar neuronal processes, differentiated human neuronal lines, and both microglial cells and astrocytes in human brain cultures. Thus the inventors sought to identify novel short chemokine peptides which would be antagonists of gp120-mediated neurotoxicity and resultant neuronal degeneration and thereby provide therapeutic benefits in patients suffering from HIV infection, or other inflammatory neurological diseases such as multiple sclerosis, tropical spastic paraparesis, and Alzheimers, to cite some.
It is an object of the present invention to provide peptides and a method for treating diseases having symptoms caused by neuronal cell death caused by HIV, MS, Alzheimers"" Disease, PML, and Tropical Spastic Paraparesis, among others.
It is another object to provide a pharmaceutical composition having a peptide as an active agent for reducing or inhibiting neuronal cell loss.
These and other objects of the present invention are achieved by a peptciode of the formula
Leu-Glu-Ser-Tyr-Thrxe2x80x83xe2x80x83(SEQ. ID NO: 1)
or
Ile-Lys-Glu-Tyr-Phe-Thr-Serxe2x80x83xe2x80x83(SEQ. ID: 2)
A method for treating the symptoms associated with neuronal cell death in a person caused by a neurological degenerative disease comprises administering a therapeutically effective amount of a peptide of the formula
Leu-Glu-Ser-Tyr-Thrxe2x80x83xe2x80x83(SEQ. ID NO: 1)
or
Ile-Lys-Glu-Tyr-Phe-Thr-Serxe2x80x83xe2x80x83(SEQ. ID NO: 2)
The invention comprises a peptide of the formula Leu-Glu-Ser-Tyr-Thr (SEQ. ID NO:1) or Ile-Lys-Glu-Tyr-Phe-Thr-Ser (SEQ. ID NO: 2) or a physiologically acceptable salt thereof. A pharmaceutical composition comprising as a active ingredient at least one peptide of the formula Leu-Glu-Ser-Tyr-Thr (SEQ. ID NO: 1) or Ile-Lys-Glu-Tyr-Phe-Thr-Ser (SEQ. ID NO: 2) or a pharmaceutically, acceptable salt thereof, for treating the symptoms caused by neuronal cell loss. The pharmacutical composition can further comprise a pharmaceutically acceptable carrier.
The invention also includes a method for treating the symptoms caused by a loss of neurons comprising administering to a person suffering from a disease causing neuronal cell loss a therapeutically effective amount of a peptide of formula Leu-Glu-SER-Tyr-Thr (SEQ. ID NO: 1) or Ile-Lys-Glu-Tyr-Phe-Thr-Ser (SEQ. ID NO: 2) or pharmaceutically acccptitble salt thereof. The method can comprise either the formula Leu-Glu-Ser-Tyr-Thr (SEQ. ID NO: 1) or Ile-Lys-Glu-Tyr-Phe-Thr-Ser (SEQ. ID. NO: 2). According to the method, the peptide is administered by oral, intranasal, buccal, parenteral, topical or rectal administration.